Trends in 505(b)(2) Approvals
The who, what, why, when and how of this hybrid application process
By Loren Gelber
The 505(b)(2) NDA is a type of new drug application that was created by the amendments to the Food, Drug and Cosmetic Act of 1984, commonly referred to as Waxman-Hatch (or Hatch-Waxman when Republicans have the upper hand)1. This type of application is intermediate between the full NDA required for a new drug that is a new chemical entity never before approved in the U.S. and an ANDA used to get generic drugs approved. Some of the information needed for approval of a 505(b)(2) NDA is not owned by the applicant, but may be either a reference to information in the application of a reference-listed drug, or taken from the published scientific literature2.
Because the development of a product for a 505(b)(2) NDA is much less expensive than that of an NDA involving a new chemical entity, smaller firms are more likely to be interested in these types of submissions. Such firms are unlikely to have the ability to conduct all of the required work in house, so they will require contract services.
To see how this tool has been used in the last 24 years, an analysis of NDAs approved under the 505(b)(2) provisions was conducted. The data used to write this article comes from the website Drugs@FDA. It is based on those approvals that are designated as 505(b)(2) in their approval letters posted on this site.
At least 185 505(b)(2) NDAs have been approved by FDA since the Waxman-Hatch amendments to the FD&C act became effective in September of 1984. The first was Mylan Bertek Maxide, approved October 22, 1984. This application was clearly pending when the amendments became effective, so that FDA could convert its status of a 505(b)(2) NDA and approve it. Only five 505(b)(2) NDAs were approved between 1984 and 1996. Five more were approved in 1997 and 1998. Starting in 2002, the number of approvals began to increase dramatically, as can be seen in Figure 1 below.
|Figure 1: Number of 505(b)(2) NDAs approved each year
Table 1: Firms that have received three or more approvals of 505(b)(2) NDA as of 12/09
|Firm||# of 505(b)(2) NDA approved as of 7/09|
|* Tentative approvals for the President’s Emergency Program for Aids Relief (PEPFAR).|
|** All for Colchicine|
Only three of the 14 firms in Table 1 market generic drugs as a major part of their business. Several of the firms listed are “innovator” or member firms of the Pharmaceutical Research and Manufacturers of America (PhRMA). A similarly diverse group of firms have received one or two approvals of 505(b)(2) NDAs.
Table 2: The percentage of 505 (b)(2) NDAs approved by dosage form.
|Dosage Form||% of total|
|DR = delayed release|
|ER = extended release|
|IR = immediate release|
|ODT = orally dissolving tablet|
While immediate release tablets are the largest category of dosage forms approved, they do not predominate to the extent that they do in the pharmaceutical marketplace. The 505(b)(2) NDA has been used extensively to obtain approval of alternate dosage forms, as will be discussed further below.
A more extensive review was conducted of approximately 115 505(b)(2) NDAs approved between 1998 and 2009, for which the FDA review documents are available at the web site Drugs@FDA. Approximately 30% of these NDAs were for dosage forms that differ from those of the reference-listed drug. About 15% were for new combinations of active ingredients.
Alternative molecular forms of the active pharmaceutical ingredient — such as new counterions or acid instead of salt — have been approved as 505(b)(2) NDAs.Older products, variously designated “grandfather,” DESI, or “illegal,” have also been approved using this pathway, notably 8-levothyroxine-sodium applications.
Approval via the 505(b)(2) route has been obtained for products with better absorption or better delivery systems than their reference-listed drugs, different vehicles or actuators, formulations, indications, potencies, preservatives, propellants, release patters and routes of administration. Two “biosimilars,” Sandoz’s Cosyntropin and Omnitrope, were approved as 505(b)(2)s because their reference-listed drugs were drugs rather than biologicals. Several products were approved based on information from submissions to the EU or Australia, or based on extensive published literature.
Of the 115 products whose review documents were available on line, slightly less than 10% of them were approved with no human or animal studies. Except for Thalomid capsules, all the others were parenteral formulations, so that no pharmacokinetic studies were required.Only pharmacokinetic studies — but neither animal nor clinical studies — were submitted for the approval of an additional 30% (approximately) of the applications. In most to all of these cases, there was sufficient published literature about the active ingredients and often also dosage forms involved. The reference-listed drugs were often of relatively recent approval, so the FDA could consider them as meeting current standards for safety and efficacy. About 10% of the applications were approved with one well-controlled clinical trial, including several topicals that were approved based on one bioequivalence trial with a clinical endpoint.These applications represent about half of all those approved as 505(b)(2) NDAs. The remaining half had between two and 22 clinical trials submitted in their applications, between zero and 25 pharmacokinetic studies and between zero and 35 preclinical animal studies.
In order to decide how to proceed with a 505(b)(2) application, an extremely thorough review of available literature is required. It is then advisable to carefully plan the required studies, so that the most cost-effective program is conducted. It is highly advisable for firms, especially those not very experienced in this area, to consult experts to guide them to the most efficient methods and procedures.
One may conclude from the information above that the 505(b)(2) NDA approval process is a very powerful tool for obtaining approval of a unique pharmaceutical product without the time and expense needed to complete the “full” NDA approval process. The range of products that have been approved by this route is very broad. Various types of pharmaceutical firms are starting to take more advantage of the 505(b)(2) NDA. It is notable that 47% of the NDAs that were approved in 2009 were 505(b)(2) submissions. One may anticipate even more use of this approval route in the future.
- The Drug Price Competition and Patent Term Restoration Act of 1984, United States Congress.
- Berry, IR and Martin, RP, editors, The Pharmaceutical Regulatory Process, 2nd Edition, Informa Healthcare, New York, 2008, Chapter 4.